The candidate is a trained dentist and his research experience is in the fields of dentin and bone developmental biology, where his main interests have been in dentin matrix proteins and bone morphogenetic protein receptors, in vitro/ in vivo gene function. The candidate has been trained in US in the field of molecular biology with high quality publications, and his long-term goal is to become an independent investigator, capable of directing high quality academic research in his research field. In addition to didactic courses, the candidate will learn several new research techniques through the duration of Award, such as gene targeting skill, electron microscopes skill, pulp cell culture, and tooth germ culture. Dentinogenesis requires the precise spatial and temporal coordination of programs for cell growth, differentiation, and mineralization. If one of these programs is interrupted or perturbed, tooth defects will likely occur. In a search for genes required for normal dentin morphogenesis we have studied Dentin matrix protein 1 (DMP1) using an in vivo loss-of-function approach. Dmp1 null mice display profound tooth abnormalities, suggesting that DMP1 is required for normal dentinogenesis. Recent studies suggest that proteolytically processed fragments of DMP1 are responsible for its bioactivity. We propose that DMP1, an ECM protein highly active in odontoblasts, plays a key role in controlling dentinogenesis through its proteolytically processed forms. To test the hypothesis, transgenic approaches will be used to determine the ability of full-length DMP1 and its fragment to rescue the phenotype of Dmp1 null mice. In Aim 1 the tooth defects in mice lacking DMP1 will be characterized in detail and in relation to tooth morphogenesis. In Aim 2 the function of intact DMP1 will be determined by transgenic over-expression and rescue approaches using the Dmp1 null mice. Completion of these experiments during Scholar Development phase will set a solid foundation to further test the functional fragments of this protein in dentinogenesis in the Faculty Transition Phase. In Aim 3 in vivo function of cleaved fragment of DMP1 will be studied by re-expressing in Dmp1 null mice. In Aim 4 in vivo function of mutated DMP1 will be studied. Finishing the whole project will enhance our understanding of the molecular mechanisms of tooth morphogenesis and will identify novel targets for therapeutic intervention of dental diseases.